1. Field of the Invention
The present invention relates to pharmaceutical compositions comprising calcitonin and to a spray unit for the intranasal administration of said compositions.
More particularly, the invention relates to pharmaceutical compositions whose active ingredient is calcitonin, which compositions are free from preservants and surfactants.
Still more particularly, the invention relates to pharmaceutical compositions for intranasal administration, comprising calcitonin--preferably salmon calcitonin--dissolved in physiological saline adjusted to pH 3.5-4.5 by means of hydrochloric acid.
2. Description of the Prior Art
Calcitonins are known to be of basic importance in the treatment of osteoporosis, Paget's disease, hypercalcemia and similar pathological conditions. Calcitonins are also known to undergo degradation easily, due to the polypeptide nature thereof; as a consequence, they cannot be administered by the oral route. On the other hand, parenteral administration of calcitonins by injection involves remarkable disadvantages, particularly painful reactions in the patient.
Intranasal administration of polypeptide drugs is also widely described in literature; see, e.g., Felber et al., Experientia, 1969, page 1195; Gennser et al., Lancet, 1974, page 865; Greenberg et al., Antimicrobial Agents and Chemotherapy, 1978, page 596; Bergquist et al., Lancet, 1979, page 215; Pontiroli et al., British Medical Journal, 1982, page 303, besides a number of patents or patent applications concerning intranasal administrations of insulin (EP 94157), vasopressin (Japanese Patent applications 55066-517, 55055-120), polypeptides of various nature (German Patents 2.256.445 and 2.758.483, EP 252, Belgian Patent 860.717, South African Patent 68/4241).
Intranasal administration of calcitonin is in its turn disclosed in various patents. Thus, Italian Patent 1.172.324 claims galenic compositions comprising calcitonin characterized in that they contain, besides the active ingredient, benzalkonium chloride or a surfactant, particularly a non-ionic surfactant, or both the above additives. Higher alkanols or sterol polyoxyalkylene ethers are particularly claimed as surfactants.
Both surfactants and benzalkonium chloride are indicated to be necessary ingredients to provide a good calcitonin bioavailability, that is to assure the effective adsorption thereof by nasal mucosa, while benzalkonium chloride would also act as a preservant against pathogen or undesirable micro-organisms.
Similar compositions containing a quaternary ammonium salt (benzalkonium chloride, cetyltrimethylammonium bromide) are claimed in EP-A-193.372. Japanese Patent Application 61126-034 discloses nasal formulations of calcitonin containing absorption-increasing agents such as glucose and/or glucosamine. The need for an absorption adjuvant is also stressed by Japanese Patent Application 61118-325, which proposes for this purpose the addition of amino acids, and by EP-A-183.527, which suggests the use of benzyl alcohol, ethanol, salicylic acid, capronic acid, polyethylene glycol and the like as absorption enhancers. Moreover, EP-A-111.841 and EP-A-115.627 claim intranasal compositions containing calcitonin in admixture with surfactants, among which biliary acids and benzalkonium chloride are disclosed.
Nevertheless, the presence of the latter--and generally of quaternary ammonium salts--is not satisfactory due to the possible undesired effects thereof; see, e.g., Am. J. Ophthalmol., Jun. 15, 1988, vol. 105 (6), pp. 670-3; Contact Dermatitas, July 1987, vol. 17 (1), pp 41-2; and Cutis, May 1987, vol.39 (5), pp. 381-3. Therefore, it would seem to be better to provide intranasal compositions of calcitonin free from said salts. However, according to some of the above mentioned documents, said compositions would suffer from poor bioavailability.
All the patent documents reported above completely agree on the need to enhance said bioavailability by means of surfactants of various natures which promote calcitonin absorption through nasal mucosa.